Role of oestrogen therapy in the management of short stature in Turner syndrome

It is now clear that parenteral growth hormone (GH) therapy stimulates growth and increases the adult stature of girls with Turner syndrome. In addition, oestrogens are given to almost all girls with this syndrome because of primary hypogonadism. Oestrogens influence both growth and maturation of the epiphyseal growth plates. Therefore, the form and timing of oestrogen therapy may have an important impact on the outcome of other growth-promoting therapies. To examine the impact of the timing of oestrogen initiation on growth, a randomized trial was conducted in patients with Turner syndrome who were receiving GH. Some patients received oestrogen at 12 years of age, while in others this treatment was not started until 15 years of age. Those girls that received oestrogen later were significantly taller as adults. The single most important factor in determining height gain appeared to be the number of years of GH therapy prior to the initiation of oestrogen treatment.     

Final height outcome in girls with Turner syndrome treated with a combination of low dose oestrogen and oxandrolone

Final stature in girls with Turner syndrome treated with combination of low dose oestrogen and oxandrolone. Nineteen prepubertal girls with Turner syndrome (mean age 10.9 years, range, 8.9–14.2 years) were randomly assigned to receive either oxandrolone (0.05 mg/kg/day) or ethinyloestradiol (40 ng/kg/day) for 1 year. Subsequently the alternate therapy was added and the combination given until attainment of final height. Ethinyloestradiol was gradually increased at the age of 12.5 years in order to induce secondary sexual characteristics. The duration of treatment was a mean of 5.2 years (range, 3–7 years) when the 1st year of monotherapy was included. Therapy produced a sustained acceleration in growth rate for a duration of 4 years and eventually has resulted in an increment of mean adult height of 3 cm relative to pre-treatment projected height with mean values of 146.5 cm versus 143.5 cm respectively. The moderate side-effects observed did not cause any of the girls to discontinue treatment. Nevertheless, amelioration of adult height appears to be modest, notably in comparison to published data of growth hormone treatment and 4 girls had a decrease in final height prediction. Conclusion Combination of low dose of oxandrolone and oestrogen may have a moderate but positive impact on final height in girls with Turner syndrome. However, some girls do worse than predicted in term of final height using this regimen. Oestrogen therapy started at low dose around the age of 10 years and increased gradually at approximately 12.5 years to induce secondary sexual characteristics does not have a deleterious effect on adult height in Turner syndrome. In summary, low dose oxandrolone-oestrogen treatment was found to accelerate the tempo of growth in girls with Turner syndrome, but did not appear to have a consistent effect on final height. Received: 22 July 1996 / Accepted: 22 October 1996     

A multicentre trial of recombinant growth hormone and low dose oestrogen in Turner syndrome: near final height analysis.

BACKGROUND: Turner syndrome accounts for 15-20% of childhood usage of growth hormone (GH) in the UK but final height benefit remains uncertain. The most effective strategy for oestrogen replacement is also unclear. METHODS: Fifty eight girls who, at start of treatment, were of mean age 9.1 years and projected final height 142.2 cm were randomised to receive in year 1, either low dose ethinyloestradiol 50-75 ng/kg/day, GH 28 IU/m(2) surface area/week as a daily injection, or a combination of ethinyloestradiol and GH. After the first year, the ethinyloestradiol treated girls received combination treatment. After two years, girls aged over 12 years were given escalating ethinyloestradiol to promote pubertal development. RESULTS: Near final height was available for 49 girls at age 16.5 years, 146.8 cm, representing a gain of 4.6 cm, range -7.9 to +11.7 cm. Twelve of the 49 girls gaining 7.5 cm or more were less than 13 years at the start and had received GH for at least four years. Height gain was correlated with greater initial height deficit. Fifteen girls (31%) reached 150 cm or more compared to a predicted 10%. Early supplementation with ethinyloestradiol provided no final height advantage. CONCLUSIONS: Final height gain was modest at 4.6 cm. Younger, shorter girls gained greatest height advantage from GH. Low dosage ethinyloestradiol before planned induction of puberty was not beneficial.     

A multicentre trial of recombinant growth hormone and low dose oestrogen in Turner syndrome: near final height analysis

BACKGROUND—Turner syndrome accounts for 15-20% of childhood usage of growth hormone (GH) in the UK but final height benefit remains uncertain. The most effective strategy for oestrogen replacement is also unclear.METHODS—Fifty eight girls who, at start of treatment, were of mean age 9.1 years and projected final height 142.2 cm were randomised to receive in year 1, either low dose ethinyloestradiol 50-75 ng/kg/day, GH 28 IU/m² surface area/week as a daily injection, or a combination of ethinyloestradiol and GH. After the first year, the ethinyloestradiol treated girls received combination treatment. After two years, girls aged over 12 years were given escalating ethinyloestradiol to promote pubertal development.RESULTS—Near final height was available for 49 girls at age 16.5 years, 146.8 cm, representing a gain of 4.6 cm, range ?7.9 to +11.7 cm. Twelve of the 49 girls gaining 7.5 cm or more were less than 13 years at the start and had received GH for at least four years. Height gain was correlated with greater initial height deficit. Fifteen girls (31%) reached 150 cm or more compared to a predicted 10%. Early supplementation with ethinyloestradiol provided no final height advantage.CONCLUSIONS—Final height gain was modest at 4.6 cm. Younger, shorter girls gained greatest height advantage from GH. Low dosage ethinyloestradiol before planned induction of puberty was not beneficial.     

Favorable Impact of Growth Hormone Treatment on Cholesterol Levels in Turner Syndrome

Background: Patients with Turner syndrome (TS) are prone to having metabolic abnormalities, such as obesity, dyslipidemia, hypertension, hyperinsulinemia and type 2 diabetes mellitus, resulting in increased risks of developing atherosclerotic diseases. Objective: To determine the effect of growth hormone (GH) therapy on serum cholesterol levels in prepubertal girls with TS enrolled in the Turner syndrome Research Collaboration (TRC) in Japan. Patients and methods: Eighty-one girls with TS were enrolled in the TRC, and their total cholesterol (TC) levels before GH therapy were compared with reported levels of healthy school-aged Japanese girls. TC levels after 1, 2 and 3 yr of GH treatment were available for 28 of the 81 patients with TS. GH was administered by daily subcutaneous injections, 6 or 7 times/wk, with a weekly dose of 0.35 mg/kg body weight. Results: Baseline TC levels revealed an age-related increase in TS that was in contrast to healthy girls showing unchanged levels. During GH therapy, TC decreased significantly after 1 yr of GH treatment and remained low thereafter. Conclusions: Girls with untreated TS showed an age-related increase in TC that was a striking contrast to healthy girls, who showed unchanged levels. GH therapy in girls with TS brought about a favorable change in TC that indicates the beneficial impact of GH on atherogenic risk.     

Methionyl human growth hormone and oxandrolone in Turner syndrome: preliminary results of a prospective randomized trial

Seventy girls with Turner syndrome, 4 to 12 years of age, were randomly assigned to receive either no treatment (control) or methionyl human growth hormone (0.125 mg/kg three times per week), oxandrolone (0.125 mg/kg/day), or combination hGH plus oxandrolone therapy. Baseline growth rates averaged 4.3 cm/yr, and all were within 2 SD of mean growth velocity for age in girls with Turner syndrome. Sixty-seven girls remained in the study for a minimum of 1 year. Growth rates and growth velocity (in standard deviations for age in girls with Turner syndrome) were control 3.8 cm/yr (-0.1 SD), hGH 6.6 cm/yr (+2.3 SD), oxandrolone 7.9 cm/yr (+3.7 SD), and combination therapy 9.8 cm/yr (+5.4 SD). Mean bone ages advanced 1.0 years (hGH), 1.3 years (oxandrolone), and 1.6 years (combination). However, median increments in height age/bone age (delta HA/delta BA) ratios ranged from 1.0 to 1.1 for treatment groups, compared with 0.8 for the controls. Predicted adult height by the method of Bayley-Pinneau increased 2.5 cm for hGH or oxandrolone alone, and 3.2 cm for combination treatment. These data indicate that both hGH and oxandrolone can significantly stimulate short-term skeletal growth in patients with Turner syndrome, and potentially increase final adult height.     

Predicting the response to recombinant human growth hormone in Turner syndrome: KIGS models. KIGS International Board. Kabi International Growth Study

A mathematical model for predicting the growth response in patients with Turner syndrome who received growth hormone (GH) therapy was developed by analysing data from KIGS, the Pharmacia & Upjohn International Growth Database. A model for year 1 of GH therapy explained 46% of the variability of the growth response, with GH dose being the most important of the predictors of height velocity. In years 2-4 of therapy, height velocity during the previous year was the most important predictor, suggesting that an individual's initial response to GH may determine the height outcome of treatment. Additional predictors of height velocity in years 1-4 of GH therapy included age (negative), weight SDS and additional treatment with oxandrolone. The predictions in all 4 years were highly accurate, as indicated by the low error SDs. However, relatively low predictive power (R) during years 2-4 of treatment suggests the models are missing other parameters that would explain more of the variability of the growth response. These growth prediction models could help clinicians to design individualized treatment regimens, provide realistic expectations of therapy outcomes, and adjust treatment on the basis of detected differences between observed and predicted height velocities.     

A decade of growth hormone treatment in girls with Turner syndrome in the UK. UK KIGS Executive Group.

Fifteen per cent of children treated with growth hormone (GH) are receiving treatment for Turner syndrome, but few results are available on final height in the UK. In this study, data were obtained from the UK KIGS database for 485 girls with Turner syndrome who were treated from 1986, allowing an audit of practice and outcome over 10 years. Over the decade, the mean age of starting growth hormone treatment fell from 10.4 to 8.5 years and the starting dose increased from 0.55 to 0.95 IU/kg/week. The frequency of injections increased from three to six or seven/week. Some girls received suboptimal doses, which also differed depending on whether they were based on weight or surface area. To assess what height gain might be expected at final height, all 52 girls who were prepubertal at the start of treatment, which continued for four years or more, and who had reached final height or had a growth velocity < 2 cm/year were selected. Their mean gain in final height was 5.2 cm and the GH dose was 0.78 IU/kg/week over 5.8 years. Final height gain correlated significantly with duration of treatment, total dose received, and first year response, which itself related to starting dose. This audit shows a changing pattern of treatment over the past decade, which in many instances has been inadequate. When treatment starts before puberty and continues through to final height, with a dose of 30 IU/m2/week in six or seven injections, a mean increase in final height of 5 cm or more would be expected.     

Growth curve for girls with Turner syndrome.

A growth chart for girls with Turner syndrome has been prepared using data from four published series of European patients, and evaluated using retrospective data on the heights of girls with Turner syndrome seen at this hospital. The results indicate that calculation of height standard deviation score from this chart allows a reasonable prediction of adult stature in any patient with Turner syndrome. In addition, the results indicate that while oestrogen treatment causes an initial acceleration of growth, it has no significant effect on adult height.     

A decade of growth hormone treatment in girls with Turner syndrome in the UK

Fifteen per cent of children treated with growth hormone (GH) are receiving treatment for Turner syndrome, but few results are available on final height in the UK. In this study, data were obtained from the UK KIGS database for 485 girls with Turner syndrome who were treated from 1986, allowing an audit of practice and outcome over 10 years. Over the decade, the mean age of starting growth hormone treatment fell from 10.4 to 8.5 years and the starting dose increased from 0.55 to 0.95 IU/kg/week. The frequency of injections increased from three to six or seven/week. Some girls received suboptimal doses, which also differed depending on whether they were based on weight or surface area. To assess what height gain might be expected at final height, all 52 girls who were prepubertal at the start of treatment, which continued for four years or more, and who had reached final height or had a growth velocity < 2 cm/year were selected. Their mean gain in final height was 5.2 cm and the GH dose was 0.78 IU/kg/week over 5.8 years. Final height gain correlated significantly with duration of treatment, total dose received, and first year response, which itself related to starting dose. This audit shows a changing pattern of treatment over the past decade, which in many instances has been inadequate. When treatment starts before puberty and continues through to final height, with a dose of 30 IU/m²/week in six or seven injections, a mean increase in final height of 5 cm or more would be expected.

     

Therapie mit Wachstumshormon bei Ullrich-Turner-Syndrom

Therapy with recombinant human growth hormone (GH) of short-statured girls with Ullrich Turner syndrome (UTS) has been authorized in Germany since 1991. To date, the daily recommended GH dose has been 50 µg/kg (s.c. injection). By comparing different GH doses, it could be shown in recent years that height gain was much better in those girls who were treated with a higher GH dose than girls treated with the recommended dose. Therefore, upon request of the company Novo Nordisk, the European Medicines Agency (EMEA) recently authorized a GH dose of 46–67 µg/kg/day for the treatment of this patient population. The current report summarizes the results of an expert workshop of pediatric endocrinologists, which was held to review the present position of GH therapy in girls with Turner syndrome in light of the higher GH dose. The workshop addressed issues such as the current status of therapy, the background to the dose increase, whether the dose should be increased in general or only in certain cases, possible risks, dosage adjustments, approaches in puberty, as well as ending therapy and transition to adult medicine.     

Ganglioneuroma of left adrenal gland in a patient with Turner syndrome during growth hormone therapy

We report on a Japanese girl with Turner syndrome (45,XO) who developed ganglioneuroma of the left adrenal gland during growth hormone (GH) therapy. She had received GH replacement therapy from the age of 6.8 years. At the age of 10.3 years, abdominal ultrasonography revealed a mass which occupied the upper area of her left kidney. Computed tomography and magnetic resonance imaging of the abdomen showed a low density mass with a smooth surface located between the upper portion of the left renal vein and the pancreas. Microscopic examination resulted in a diagnosis of ganglioneuroma of the left adrenal gland. At present we cannot conclude that patients who have received GH replacement therapy are at higher risk for developing tumors compared to those without GH replacement therapy.     

Predicting the response to recombinant human growth hormone in Turner syndrome: KIGS models

A mathematical model for predicting the growth response in patients with Turner syndrome who received growth hormone (GH) therapy was developed by analysing data from KIGS, the Pharmacia & Upjohn International Growth Database. A Model for year 1 of GH therapy explained 46% of the variability of the growth response, with GH dose being the most important of the predictors of height velocity. In years 2-4 of therapy, height velocity during the previous year was the most important predictor, suggesting that an individual's initial response to GH may determine the height outcome of treatment. Additional treatment with oxandrolone. The predictions in all 4 years were highly accurate, as indicated by the low error SDs. However, relatively low predictive power ( R ) during years 2-4 of treatment suggests the models are missing other parameters that would explain more of the variability of the growth response. These growth prediction models could help clinicians to design individualized treatment regimens, provide realistic expectations of therapy outcomes, and adjust treatment on the basis of detected differences between observed and predicted height velocities.     

Growth hormone treatment in Turner syndrome accelerates growth and skeletal maturation

Sixteen girls with Turner syndrome (TS) were treated for 4 years with biosynthetic growth hormone (GH). The dosage was 4IU/m² body surface s.c. per day over the first 3 years. In the 4th year the dosage was increased to 61 U/m² per day in the 6 girls with a poor height increment and in 1 girl oxandrolone was added. Ethinyl oestradiol was added after the age of 13. Mean (SD) growth velocities were 3.4 (0.9), 7.2 (1.7), 5.3 (1.3), 4.3 (2.0) and 3.6 (1.5) cm/year before and in the 1st, 2nd, 3rd and 4th year of treatment. Skeletal maturation advanced faster than usual in Turner patients especially in the youger children. Although the mean height prediction increased by 5.6 cm and 11 of the 16 girls have now exceeded their predicted height, the height of the 4 girls who stopped GH treatment exceeded the predicted adult height by only 0 to 3.4 cm.     

Six-year results of a randomized, prospective trial of human growth hormone and oxandrolone in Turner syndrome.

Seventy girls with Turner syndrome, verified by karyotype, were randomly assigned to observation or treatment with human growth hormone (hGH), oxandrolone, or a combination of hGH plus oxandrolone for a period of 12 to 24 months, to assess the effect of treatment on growth velocity and adult height. Subsequently, all subjects received either hGH alone or hGH plus oxandrolone. Data are presented for 62 subjects treated for a period of 3 to 6 years. When compared with the anticipated growth rate in untreated patients, the growth rate after treatment with hGH, both alone and in combination with oxandrolone, showed a sustained increase for at least 6 years. Treatment is continuing in over half of the subjects; at present, 14 (82%) of 17 girls receiving hGH alone and 41 (91%) of 45 girls receiving combination therapy exceeded their expected adult heights. Thirty girls have completed treatment; mean height for these 30 patients is 151.9 cm, compared with their mean original projected adult height of 143.8 cm. We conclude that therapy with hGH, alone and in combination with oxandrolone, can result in a sustained increase in growth rate and a significant increase in adult height for most prepubertal girls with Turner syndrome.     

Growth hormone treatment regimens in girls with Turner syndrome

To optimize growth hormone (GH) treatment in girls with Turner syndrome, two multicentre studies were carried out in The Netherlands: a frequency-response study (study 2) and a dose-response study (study 2). In study 1, 19 girls with Turner syndrome, aged 11 years or older, were treated with one or two daily injections of GH at a total dose of IU/m²/day (0.067 mg/kg/day) and ethinyloestradiol given orally at a dose of 0.05 μg/kg/day. All the girls reached final height. The mean (±SD) gain in final height was not significantly different between the once- or twice-daily regimens (7.6 ± 2.3 versus 5.1 ± 3.2 cm, respectively). The mean final height attained was 155.5 ± 5.4 cm. All the girls exceeded their adult height prediction. In study 2, 68 girls with Turner syndrome, aged 2-11 years, were randomized into three dosage groups: A, B and C. During the first year, the girls in all the groups received GH at a dose of 4 IU/m²/day (0.045 mg/kg/day), which group A continued to receive throughout the study. At the start of the second year groups B and C were switched to a dose of 6 IU/m²/day, which the girls in group B continued to receive for the reminder of the study. At the start of the third year, the girls in group C were switched to a dose of 8 IU/m²/day (0.090 mg/kg/day) for the remainder of the study. After 7 years of GH treatment, height SDS (based on Turner syndrome and normal population references) increased significantly in all three groups, but significantly more in groups B and C compared with group A ( p = 0.02 and p =0.001, respectively). Predicted adult height increased significantly, without a significant difference between the three groups. The mean final heights of 25 of the girls were 159.1, 161.8 and 162.7 cm for groups A, B and C, respectively.     

New aspects of oestrogen/gestagen-induced growth and endocrine changes in individuals with turner syndrome

Patients with Turner syndrome (n=33) were subjected to a sequential oestrogen/gestagen replacement therapy (21 days 2 mg oestradiol valerate plus 0.5 mg norgestrel for 10 days) for 1–4 years. In individuals aged 12–17 years, growth velocities before treatment ranged between 2.9 and 1.9 cm/year and increased to 6.8–3.8 cm/year following sex steroid substitution for 1 year. Thereafter a decrease was observed; depending on age, pre-treatment velocities were observed within 2–4 years of replacement therapy. On average, bone age advanced 1 year following 1 year of sex steroid administration and adult bone age was reached following 2–4 years of treatment. Approximately 70% of the invididuals noted breast development to stage IV according to Tanner and experienced regular withdrawal bleedings. Oral administration of oestradiol valerate resulted in serum oestradiol levels normally seen during the early follicular phase; hypergonadotropic LH and FSH levels decreased slightly following 1 year of therapy. Growth ranged between 4 and 13 cm; in the oldest individuals the final height ranged between 149 and 156 cm.In summary, the oestrogen/gestagen replacement therapy chosen for this study achieved development of secondary sex characteristics, endocrine changes, growth velocities, bone age advancement and to a certain extent growth, which was almost comparable to that observed during puberty in healthy girls.     

Growth hormone treatment regimens in girls with Turner syndrome. Dutch Advisory Group on Growth Hormone

To optimize growth hormone (GH) treatment in girls with Turner syndrome, two multicentre studies were carried out in The Netherlands: a frequency-response study (study 1) and a dose-response study (study 2). In study 1, 19 girls with Turner syndrome, aged 11 years or older, were treated with one or two daily injections of GH at a total dose of 6 IU/m2/day (0.067 mg/kg/day) and ethinyloestradiol given orally at a dose of 0.05 microg/kg/day. All the girls reached final height. The mean (+/-SD) gain in final height was not significantly different between the once- or twice-daily regimens (7.6 +/- 2.3 versus 5.1 +/- 3.2 cm, respectively). The mean final height attained was 155.5 +/- 5.4 cm. All the girls exceeded their adult height prediction. In study 2, 68 girls with Turner syndrome, aged 2-11 years, were randomized into three dosage groups: A, B and C. During the first year, the girls in all the groups received GH at a dose of 4 IU/m2/day (0.045 mg/kg/day), which group A continued to receive throughout the study. At the start of the second year, groups B and C were switched to a dose of 6 IU/m2/day, which the girls in group B continued to receive for the remainder of the study. At the start of the third year, the girls in group C were switched to a dose of 8 IU/m2/day (0.090 mg/kg/day) for the remainder of the study. After 7 years of GH treatment, height SDS (based on Turner syndrome and normal population references) increased significantly in all three groups, but significantly more in groups B and C compared with group A (p = 0.02 and p = 0.001, respectively). Predicted adult height increased significantly, without a significant difference between the three dosage groups. The mean final heights of 25 of the girls were 159.1, 161.8 and 162.7 cm for groups A, B and C, respectively.     

Effect of low doses of estradiol on 6-month growth rates and predicted height in patients with Turner syndrome

We randomly assigned 16 girls with Turner syndrome, age 5 to 15 years, to receive treatment with 100 ng/kg/day ethinyl estradiol or placebo for 6 months, with crossover after a 2-month interim period. We assessed growth by measurement of the 4-week lower leg growth rate and by height velocity. Bone age was determined at the beginning and end of treatment. Growth rate during ethinyl estradiol treatment was approximately 70% greater than during placebo (P less than 0.001), without any bone age advancement relative to that with placebo. The change in predicted height was significantly greater after 6 months treatment with ethinyl estradiol than after treatment with placebo (mean +/- SEM, +0.35 +/- 0.38 cm vs. -0.85 +/- 0.32 cm, P less than 0.03). Breast budding occurred in six patients. We conclude that it may be feasible to begin low-dose estrogen therapy to promote growth at an earlier age than would be conventionally used to induce pubertal development. These data are still relatively short term, however; until long-term data are available, it would be premature to make definitive recommendations regarding the dose and timing of estrogen treatment in Turner syndrome.     

Liver abnormalities during growth hormone treatment

BACKGROUND: Occasional and transient increase in liver enzymes is reported during growth hormone (GH) treatment in girls with Turner syndrome (TS). METHODS: Retrospectively, the specific role of GH treatment on liver and muscular enzymes was evaluated in 78 patients (48 boys; age range 4.0-20.8 years) affected by GH deficiency (GHD) who had been treated with GH for at least 1 year (range: 1-15 years). All patients had normal serum levels of liver and muscular enzymes before GH therapy was started. RESULTS: A clinically asymptomatic and mild increase in serum transaminase levels was observed in 6 of 78 patients with GHD during GH treatment; 3 (3.8%) of the patients showed an isolated, transitory and self-limiting increase in serum liver transaminase levels which was noticed 6 to 12 months after GH treatment was started, and normalized spontaneously within 3 to 6 months, without stopping the therapy. Three additional patients showed a transitory mild increase both in aspartate aminotransferase (AST) and creatine phosphokinase (CK) which also normalized spontaneously within 3 to 6 months. The increase in transaminase levels was not related to the brand of GH preparations nor to the dosage administered. CONCLUSIONS: A mild, transient, self-limiting increase in serum transaminase may occur during GH treatment. Concomitant determination of CK serum levels may quickly differentiate muscular from hepatic hypertransaminasemia. Except for persistent cases, this condition does not generally require further investigations.